Abstract:
BACKGROUND:Breast cancer intrinsic molecular subtype (IMS) as classified by the expression-based PAM50 assay is considered a strong prognostic feature, even when controlled for by standard clinicopathological features such as age, grade, and nodal status, yet the molecular testing required to elucidate these subtypes is not routinely performed. Furthermore, when such bulk assays as RNA sequencing are performed, intratumoral heterogeneity that may affect prognosis and therapeutic decision-making can be missed. METHODS:As a more facile and readily available method for determining IMS in breast cancer, we developed a deep learning approach for approximating PAM50 intrinsic subtyping using only whole-slide images of H&E-stained breast biopsy tissue sections. This algorithm was trained on images from 443 tumors that had previously undergone PAM50 subtyping to classify small patches of the images into four major molecular subtypes-Basal-like, HER2-enriched, Luminal A, and Luminal B-as well as Basal vs. non-Basal. The algorithm was subsequently used for subtype classification of a held-out set of 222 tumors. RESULTS:This deep learning image-based classifier correctly subtyped the majority of samples in the held-out set of tumors. However, in many cases, significant heterogeneity was observed in assigned subtypes across patches from within a single whole-slide image. We performed further analysis of heterogeneity, focusing on contrasting Luminal A and Basal-like subtypes because classifications from our deep learning algorithm-similar to PAM50-are associated with significant differences in survival between these two subtypes. Patients with tumors classified as heterogeneous were found to have survival intermediate between Luminal A and Basal patients, as well as more varied levels of hormone receptor expression patterns. CONCLUSIONS:Here, we present a method for minimizing manual work required to identify cancer-rich patches among all multiscale patches in H&E-stained WSIs that can be generalized to any indication. These results suggest that advanced deep machine learning methods that use only routinely collected whole-slide images can approximate RNA-seq-based molecular tests such as PAM50 and, importantly, may increase detection of heterogeneous tumors that may require more detailed subtype analysis.
journal_name
Breast Cancer Resjournal_title
Breast cancer research : BCRauthors
Jaber MI,Song B,Taylor C,Vaske CJ,Benz SC,Rabizadeh S,Soon-Shiong P,Szeto CWdoi
10.1186/s13058-020-1248-3subject
Has Abstractpub_date
2020-01-28 00:00:00pages
12issue
1eissn
1465-5411issn
1465-542Xpii
10.1186/s13058-020-1248-3journal_volume
22pub_type
杂志文章abstract:INTRODUCTION:Mammographic density has been established as a strong risk factor for breast cancer, primarily using digitized film mammograms. Full-field digital mammography (FFDM) is replacing film mammography, has different properties than film, and provides both raw and processed clinical display representation images...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3372
更新日期:2013-01-04 00:00:00
abstract::Transforming growth factor-beta (TGF-beta) is a tumor suppressor, the function of which is compromised in many types of human cancer, including breast cancer. The tumor suppressive effects of TGF-beta are caused by potent inhibition of cell proliferation due to cell cycle arrest in the G1 phase. Such antiproliferative...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr42
更新日期:2000-01-01 00:00:00
abstract:INTRODUCTION:In 2001, data from the California Cancer Registry suggested that breast cancer incidence rates among non-Hispanic white (nHW) women in Marin County, California, had increased almost 60% between 1991 and 1999. This analysis examines the extent to which these and other breast cancer incidence trends could ha...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr1266
更新日期:2005-01-01 00:00:00
abstract::The mammary gland develops as an appendage of the ectoderm. The prenatal stage of mammary development is hormone independent and is regulated by sequential and reciprocal signaling between the epithelium and the mesenchyme. A number of recent studies using human and mouse genetics, in particular targeted gene deletion...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr776
更新日期:2004-01-01 00:00:00
abstract:INTRODUCTION:Breast cancers frequently metastasise to the skeleton where they cause osteolytic bone destruction by stimulating osteoclasts to resorb bone and by preventing osteoblasts from producing new bone. The Runt-related transcription factor 2, Runx2, is an important determinant of bone metastasis in breast cancer...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3048
更新日期:2011-10-27 00:00:00
abstract:BACKGROUND:Early life exposures, including diet, have been implicated in the etiology of breast cancer. METHODS:A nested case-control study was conducted among participants in the Nurses' Health Study who completed a 24-item questionnaire about diet during high school. There were 843 eligible cases diagnosed between o...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr583
更新日期:2003-01-01 00:00:00
abstract::Recent studies indicate that constitutive signaling through the phosphatidylinositol 3'-kinase (PI3K) pathway is a cause of treatment resistance in breast cancer patients. This implies that patients with tumors that exhibit aberrant PI3K signaling may benefit from targeted pathway inhibitors. The first agents to make ...
journal_title:Breast cancer research : BCR
pub_type: 评论,杂志文章
doi:10.1186/bcr1307
更新日期:2005-01-01 00:00:00
abstract::Breast cancer arises from multiple genetic events that together contribute to the established, irreversible malignant phenotype. The development of inducible tissue-specific transgenics has allowed a careful dissection of the events required for induction and subsequent maintenance of tumorigenesis. Mammary gland targ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr297
更新日期:2001-01-01 00:00:00
abstract:INTRODUCTION:The neuron-glial antigen 2 (NG2) proteoglycan promotes pericyte recruitment and mediates pericyte interaction with endothelial cells. In the absence of NG2, blood vessel development is negatively impacted in several pathological models. Our goal in this study was to determine the effect of NG2 ablation on ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3174
更新日期:2012-04-24 00:00:00
abstract:BACKGROUND:Approximately 100 common breast cancer susceptibility alleles have been identified in genome-wide association studies (GWAS). The utility of these variants in breast cancer risk prediction models has not been evaluated adequately in women of Asian ancestry. METHODS:We evaluated 88 breast cancer risk variant...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-016-0786-1
更新日期:2016-12-08 00:00:00
abstract:INTRODUCTION:Tamoxifen, a selective estrogen receptor (ER) modulator, may affect cancer cell survival through mechanisms other than ER antagonism. In the present study, we tested the efficacy of tamoxifen in a panel of ER-negative breast cancer cell lines and examined the drug mechanism. METHODS:In total, five ER-nega...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-014-0431-9
更新日期:2014-09-17 00:00:00
abstract:INTRODUCTION:Experimental evidence suggests a protective role for circulating 25-hydroxyvitamin D (25(OH)D) in breast cancer development, but the results of epidemiological studies have been inconsistent. METHODS:We conducted a case-control study nested within two prospective cohorts, the New York University Women's H...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3390
更新日期:2013-02-26 00:00:00
abstract::Four trials of high-dose chemotherapy with stem cell support in breast cancer in the adjuvant and metastatic settings have shown no long-term disease-free or overall survival gain. This relative failure of a single high-dose therapy we believe opens up the development of a dose-dense approach with block scheduling as ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr262
更新日期:2001-01-01 00:00:00
abstract::The adaptor protein NHERF1/EBP50 (Na/H exchanger regulatory factor 1/ezrin-radixin-moesin-binding phosphoprotein 50) emerged recently as an important player in breast cancer progression. Consisting of two tandem PDZ domains linked to a carboxyl-terminal ezrin-binding region, NHERF1 assembles macromolecular complexes a...
journal_title:Breast cancer research : BCR
pub_type: 评论,社论
doi:10.1186/bcr1992
更新日期:2008-01-01 00:00:00
abstract:INTRODUCTION:During selective segregation of DNA, a cell asymmetrically divides and retains its template DNA. Asymmetric division yields daughter cells whose genome reflects that of the parents', simultaneously protecting the parental cell from genetic errors that may occur during DNA replication. We hypothesized that ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2754
更新日期:2010-01-01 00:00:00
abstract:INTRODUCTION:Mutations in BRCA1 and BRCA2 confer a high risk of breast cancer (BC), but the magnitude of this risk seems to vary according to the study and various factors. Although controversial, there are data to support the hypothesis of allelic risk heterogeneity. METHODS:We assessed variation in BC risk according...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr3218
更新日期:2012-07-03 00:00:00
abstract::The increasing importance of signal transducer and activator of transcription 3 (STAT3) expression in human cancers has led several laboratories to examine in detail the expression of one of its major negative regulators in oncogenesis--the T-cell protein tyrosine phosphatase, nonreceptor type 2 (PTPN2). A recent pape...
journal_title:Breast cancer research : BCR
pub_type: 评论,杂志文章,评审
doi:10.1186/bcr3437
更新日期:2013-07-31 00:00:00
abstract::Gene therapy is a therapeutic approach that is designed to correct specific molecular defects that contribute to the cause or progression of cancer. Genes that are mutated or deleted in cancers include the cancer susceptibility genes p53 and BRCA1. Because mutational inactivation of gene function is specific to tumor ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr26
更新日期:2000-01-01 00:00:00
abstract::In recent years it has become clear that cancer cells within a single tumor can display striking morphological, genetic and behavioral variability. Burgeoning genetic, epigenetic and phenomenological data support the existence of intra-tumor genetic heterogeneity in breast cancers; however, its basis is yet to be full...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr3658
更新日期:2014-05-20 00:00:00
abstract:BACKGROUND:Chromogenic in situ hybridization (CISH) is emerging as a practical, cost-effective, and valid alternative to fluorescent in situ hybridization in testing for gene alteration, especially in centers primarily working with immunohistochemistry (IHC). METHODS:We assessed Her-2/neu alteration using CISH on form...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr915
更新日期:2004-01-01 00:00:00
abstract:BACKGROUND:Acquirement of resistance is always associated with a highly aggressive phenotype of tumor cells. Recent studies have revealed that Annexin A2 (Anxa2) is a key protein that links drug resistance and cancer metastasis. A high level of Anxa2 in cancer tissues is correlated to a highly aggressive phenotype. Inc...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-019-1147-7
更新日期:2019-05-22 00:00:00
abstract:INTRODUCTION:Insulin-like growth factor binding protein-3 (IGFBP-3) differentially modulates breast epithelial cell growth through insulin-like growth factor (IGF)-dependent and IGF-independent pathways and is a direct (IGF-independent) growth inhibitor as well as a mitogen that potentiates EGF (epidermal growth factor...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr963
更新日期:2005-01-01 00:00:00
abstract:INTRODUCTION:Breast cancer is genetically and clinically a heterogeneous disease. However, the exact contribution of different cell types and oncogenic mutations to this heterogeneity are not well understood. Recently, we discovered an interaction between Wnt and integrin-linked kinase (ILK) within the signaling cascad...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2592
更新日期:2010-01-01 00:00:00
abstract:BACKGROUND:Mesenchymal transformation of pulmonary endothelial cells contributes to the formation of a metastatic microenvironment, but it is not known whether this precedes or follows early metastasis formation. In the present work, we characterize the development of nitric oxide (NO) deficiency and markers of endothe...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-018-1013-z
更新日期:2018-08-03 00:00:00
abstract::A small proportion of breast cancers are due to a heritable predisposition. Recently, two predisposition genes, BRCA1 and BRCA2, have been identified and cloned. The morphological features of tumours from patients harbouring mutations in the BRCA1 and BRCA2 genes differ from each other and from sporadic breast cancers...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章,评审
doi:10.1186/bcr10
更新日期:1999-01-01 00:00:00
abstract:BACKGROUND:Dysregulated DNA repair and cell proliferation controls are essential driving forces in mammary tumorigenesis. BCCIP was originally identified as a BRCA2 and CDKN1A interacting protein that has been implicated in maintenance of genomic stability, cell cycle regulation, and microtubule dynamics. The aims of t...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-017-0907-5
更新日期:2017-10-18 00:00:00
abstract:INTRODUCTION:The HER (human EGFR related) family of receptor tyrosine kinases (HER1/EGFR (epidermal growth factor receptor)/c-erbB1, HER2/c-erbB2, HER3/c-erbB3 and HER4/c-erbB4) shares a high degree of structural and functional homology. It constitutes a complex network, coupling various extracellular ligands to intrac...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr1843
更新日期:2008-01-01 00:00:00
abstract:INTRODUCTION:The tumour-suppressive effects of transforming growth factor-beta (TGF-beta) are well documented; however, the mechanistic basis of these effects is not fully understood. Previously, we showed that a non-canonical member of the Wingless-related protein family, Wnt5a, is required for TGF-beta-mediated effec...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/bcr2244
更新日期:2009-01-01 00:00:00
abstract::RAD51C is an integral part of the DNA double-strand repair through homologous recombination, and monoallelic mutations were found in ~1.3% of BRCA1/2-negative breast cancer (BC) and/or ovarian cancer (OC) families. Several studies confirmed the occurrence of RAD51C mutations predominantly in BC and/or OC families, alt...
journal_title:Breast cancer research : BCR
pub_type: 信件
doi:10.1186/bcr3589
更新日期:2013-12-20 00:00:00
abstract:INTRODUCTION:Estrogen forms a complex with the estrogen receptor (ER) that binds to estrogen response elements (EREs) in the regulatory region of estrogen-responsive genes and regulates their transcription. Sequence variants in the regulatory regions have the potential to affect the transcription factor-regulatory sequ...
journal_title:Breast cancer research : BCR
pub_type: 杂志文章
doi:10.1186/s13058-014-0455-1
更新日期:2014-10-09 00:00:00